The colon is being viewed as a promising site of drug delivery owing to its long transit time (up to 78 hrs), which is likely to increase the time available for drug absorption. Progesterone (PG) has a short elimination half-life (~19-95 min) and undergoes extensive first-pass hepatic metabolism which results in very low oral bioavailability (~25%). The aim of this work was to study the feasibility of preparing PG-loaded colon-targeted microparticles (MP's) to overcome the shortcomings associated with the oral administration of PG. MP's were prepared by the modified ionotropic gelation technique using sodium carboxymethylcellulose (NaCMC)/pectin mixture as a biodegradable matrix, zinc acetate and aluminum sulfate as cross-linkers. A 24 full factorial design was carried out to optimize the experimental conditions with the investigated factors being: polymer concentration (X¬1), drug concentration (X2), Zn(CH3COO)2 concentration (X3) and Al2(SO4)3 concentration (X4). The prepared MP's were investigated under conditions mimicking mouth-to-colon transit and the effect of the afore-mentioned factors on the release and surface characteristics of MP's has been studied. The results obtained implied that, regardless of the concentration of cross-linking agents, the polymer and drug concentrations exhibited the greatest influence on the drug entrapment efficiency (EE), which decreased as the drug concentration decreased from 1 to 0.5% w/v (95.13% and 83.88% respectively) and as the polymer concentration increased from 1.25 to 1.5% w/v (107.35% and 95.13% respectively). On the other hand, MP's prepared with 1% drug showed a significantly slower release rate than those prepared with 0.5% drug as indicated by the values of Mean Dissolution Time (MDT) & the release rate constant(k). This study confirms the viability of the prepared microparticles as a colon-targeted drug delivery system.